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以进化为指导的抗生素的发现抑制了糖的重塑
Elizabeth J Culp1, Nicholas Waglechner1, Wenliang Wang1
1M. G. DeGroote Institute for Infectious Disease Research, David Braley Centre for Antibiotic Discovery, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Nature
|February 14, 2020
概括
研究人员发现了两种新型的糖抗生素,即康普莱斯塔丁和科尔波米,通过抑制细胞壁的重塑来对抗耐药细菌. 这些化合物具有较低的耐药性,对小鼠的MRSA感染有效.
科学领域:
- 微生物学
- 生物化学
- 药物发现
背景情况:
- 抗生素耐药性的增加需要具有独特作用机制的新型抗菌化合物.
- 细菌是一种丰富的抗生素来源,但传统的查方法通常会产生已知的化合物.
- 对Actinomycetes的基因组分析揭示了许多生物合成基因集群,有可能发现新的代谢物.
研究的目的:
- 确定具有新作用机制的新型糖抗生素,以应对抗生素危机.
- 利用生物合成基因的基因分析和缺乏耐药性决定因素来预测有前途的抗生素候选者.
- 描述新发现的糖抗生素的作用模式和疗效.
主要方法:
- 利用生物合成基因的基因组和缺乏耐药性决定因素来预测新型糖抗生素候选者.
- 选了具有新生物活动潜力的糖家族的分离成员.
- 通过评估化合物与糖的结合及其对自解素活性的影响来研究作用机制.
- 在对甲素耐药黄金葡萄球菌 (MRSA) 皮肤感染的小鼠模型中评估了已识别的化合物的疗效.
主要成果:
- 鉴定出两种糖抗生素, 康普莱斯塔丁和一种新型化合物,
- 通过结合糖和阻断自解素活性,证明了康普莱斯和菌素抑制了细菌细胞壁的重塑.
- 观察到低水平的耐药性发展对菌素和康普莱斯.
- 在小鼠MRSA皮肤感染模型中,当用菌素和康普莱斯治疗时,显著降低了细菌负担.
结论:
- 康普莱斯塔丁和科尔胺是一种新型的糖抗生素,其作用机制针对细菌自解酶.
- 这些化合物为对抗耐药细菌感染提供了有前途的策略,
- 使用基因组和遗传学数据的预测方法对于发现新生物活性天然产品是有效的.
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